PROJECT SUMMARY/ABSTRACT This proposal will apply an innovative metabolic imaging approach, hyperpolarized (HP) 1-13-C MRI to address NF-kB activation in cancer. NF-kB is a key pro-survival transcriptional regulator that drives resistance in a variety of malignancies, one of which is primary CNS lymphoma (PCNSL) a highly refractory form of activated B-cell (ABC)-type large cell lymphoma. ABC-type large cell lymphomas are an important cause of cancer-related mortality worldwide. Recent trials using targeted agents that block NF-kB activation have shown activity in PCNSL and systemic ABC-type lymphoma, yet responses last only a few months, suggesting that alternative pathways of NF-kB activation are adaptively induced to mediate resistance. We hypothesize that HP 1-13-C MRI may have particular utility in detecting clinical response, defining prognosis and target inhibition in PCNSL and can also be applied to identify effective combinatorial strategies that durably suppress NF-kB activation. In addition, we envision that this approach may be impactful in identifying biomarkers that predict efficacy of immunotherapy. Our team recently demonstrated for the first time the feasibility of HP 1-13-C MRI to image malignant glioma in patients. These studies support the potential of HP 1-13-C MRI to identify metabolites that yield impactful non-invasive biomarkers of in vivo metabolic processes in PCNSL, including resistance pathways, with markedly improved sensitivity and specificity compared to standard MRI. We have recruited a talented, multidisciplinary team to pursue this highly translational project to address key gaps in PCNSL research through pursuit of the following specific Aims: 1) Test the hypothesis that hyperpolarized (HP) [1-13-C]-metabolic MR imaging of genetically-defined, patient- derived orthotopic models of PCNSL can non-invasively evaluate depth of response to combinations of NF-kB targeting agents as well as provide an early biomarker of the emergence of resistance. 2) Test the hypothesis that HP [1-13-C] metabolic MR metrics can be developed as non-invasive biomarkers of NF-kB-activation and immunosuppression in a syngeneic, immunocompetent model of PCNSL. 3) Perform the initial proof of principle patient studies of HP 13C MRI to determine feasibility and methods of HP [1-13C] pyruvate MRI as a real time, non-invasive imaging tool for response assessment in PCNSL. We will correlate genetic markers of NF-kB activation in tumors with lactate on HP 13C MRI and lactate in cerebrospinal fluid and their relationship to progression-free survival. These studies will constitute a basis for integration of HP13C metabolic imaging in the research of PCNSL, and of ABC-type lymphomas in general, to improve detection, prognostication, identify resistance, and facilitate precision medicine. We anticipate these studies will identify novel combinations and schedules of agents that durably block NF-kB, to be tested in the clinic. These studies may also provide a rationale for implementation of tumor lactate as a novel biomarker for immunotherapy trials. Ultimately our studies may stimulate multicenter trials to evaluate HP 13C MRI in PCNSL.